Yang Yiqing, Mbikyo Muisha B, Zhang Junzhe, Zhang Yuan, Zhang Naijin, Li Zhao
Department of Cardiology, The First Hospital of China Medical University, Shenyang, 110001, China.
Cell Death Discov. 2022 Apr 5;8(1):167. doi: 10.1038/s41420-022-00977-8.
Pathological cardiac hypertrophy is a key contributor in heart failure (HF). Long non-coding RNAs (lncRNAs) and N-methyladenosine (mA) modification play a vital role in cardiac hypertrophy respectively. Nevertheless, the interaction between lncRNA and mA methylase in cardiac hypertrophy is scarcely reported. Here, we constructed a cardiac hypertrophy mouse model by transverse aortic constriction (TAC) surgery and H9c2 cell model by stimulating with AngII. We found that lncRNA MIAT mRNA level, and mA RNA methylation reading protein Ythdf2 mRNA and protein levels, were significantly increased in the cardiac hypertrophy model both in vivo and vitro. MIAT or Ythdf2 overexpression aggravated cardiac hypertrophy, and vice versa. Through bioinformatics prediction, western blotting, FISH, RNA pull-down, and RIP, we found that MIAT bound to Ythdf2 and regulated its expression. Furthermore, we discovered that Ythdf2 function was a downstream of MIAT in cardiac hypertrophy. Finally, we found that MIAT was a necessary regulator of cardiac hypertrophy due to its regulation of the Ythdf2/PPARα/CPT-1a axis. This study indicated a new hypertrophic signaling pathway: MIAT/Ythdf2/PPARα/CPT-1a. The results provided a new understanding of the MIAT and mA RNA methylation reading protein, Ythdf2, function and mechanism in cardiac hypertrophy and highlighted the potential therapeutic benefits in the heart.
病理性心脏肥大是心力衰竭（HF）的关键促成因素。长链非编码RNA（lncRNA）和N-甲基腺苷（m⁶A）修饰分别在心脏肥大中发挥重要作用。然而，lncRNA与m⁶A甲基化酶在心脏肥大中的相互作用鲜有报道。在此，我们通过横向主动脉缩窄（TAC）手术构建了心脏肥大小鼠模型，并通过用血管紧张素II（AngII）刺激构建了H9c2细胞模型。我们发现，lncRNA MIAT的mRNA水平以及m⁶A RNA甲基化阅读蛋白Ythdf2的mRNA和蛋白水平在体内和体外的心脏肥大模型中均显著增加。MIAT或Ythdf2的过表达加剧了心脏肥大，反之亦然。通过生物信息学预测、蛋白质免疫印迹法（western blotting）、荧光原位杂交（FISH）、RNA下拉实验和RNA免疫沉淀实验（RIP），我们发现MIAT与Ythdf2结合并调节其表达。此外，我们发现Ythdf2的功能是MIAT在心脏肥大中的下游作用。最后，我们发现MIAT因其对Ythdf2/过氧化物酶体增殖物激活受体α（PPARα）/肉碱棕榈酰转移酶-1α（CPT-1a）轴的调节作用而成为心脏肥大的必要调节因子。本研究表明了一条新的肥大信号通路：MIAT/Ythdf2/PPARα/CPT-1a。这些结果为MIAT和m⁶A RNA甲基化阅读蛋白Ythdf2在心脏肥大中的功能和机制提供了新的认识，并突出了其在心脏方面潜在的治疗益处。
